This invention relates to a process for the stereospecific reduction of quinidinone to quinidine.
Quinidine is a dextrorotatory stereoisomer of quinine which is pharmacologically useful as an antiarrhythmic in treating heart irregularities. It is found naturally in cinchona bark but only in amounts up to 3% so that its commercial exploitation has required alternate means of supply. Such means have commonly involved variations of the Oppenhauer oxidation and Meerwein-Ponndorff reduction reactions (see for example, German Pat. Nos. 833,154 and 877,611), but in each instance, the known reactions produce four principal reaction products--quinine and its C.sub.9 epimer, epiquinine, quinidine and its C.sub.9 epimer, epiquinidine, as well as the intermediates of the C.sub.9 ketone form, quininone and quinidinone, all of which are in equilibrium in solution passing through a common transitory state. When such epi-bases are present, even in small amounts, they significantly slow crystallization of quinine and quinidine from saturated solutions, and thus lower the yields of such substances. In addition, it has been demonstrated that such epi-bases cannot be recycled like quinine under the conditions of the reaction. Indeed, a mixture of quinine and epiquinine will not give the same equilibrium, all other conditions being the same, as a quantity of pure quinine. Consequently, considerable effort has been given to solving the problem of how to influence the equilibrium toward the formation of the desired product, i.e. quinidine, while entirely avoiding the formation of epiquinine and epiquinidine. Nevertheless, the best of such efforts have established coefficients of transformation which are not much lower than 1.20 to 1.25 kilograms of anhydrous quinine base used per kilogram of anhydrous quinidine base isolated, and required the recycling of about 40% to 50% of the quinine used in the synthesis. Of course, such recycling processes generate considerably higher production costs, since they include treating the mother liquors, separating unreactive quinine and purifying it before returning it to the reaction. In some cases, because of these higher costs, it has proven to be more economical to follow a quantitative synthesis without recycling of the starting material.
Recently, attempts have been made to utilize certain aluminum hydrides in the total synthesis of a series of alkaloids belonging to the quinine and quinidine family. In particular, the reduction of quinidinone to quinidine using diisobutylaluminum hydride in toluene has been described (see Grethe, et al., J. Am. Chem. Soc. 93, 5904 (1971)). However, these methods have not solved the problems resulting from the presence of unwanted by-products since, besides quinidine, such by-products as quinine and the epi-bases are produced by such methods in unacceptable amounts; for example, 35% of such by-products were produced in the process described in the above-mentioned reference. Furthermore, such by-products are found in equal proportions, a situation which is incompatible with economical production.